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PMF belongs to the category of myeloproliferative neoplasm. It has a chronic disabling course and shortened survival. The prognostic scores IPSS, DIPSS and DIPSS-plus, do not perform as well for post-ET or post-PV MF patients. Three new prognostic systems have been recently introduced: GIPSS based exclusively on mutations and karyotype, MIPSS70 is best utilized in the absence of cytogenetic information but presence of molecular information and MIPSS70+ version 2.0 utilizes both genetic and clinical risk factors. These scores are used to aid decisions regarding eligibility for stem cell transplant.
Abbreviation: PMF: Primary Myelofibrosis; EMH: Extramedullary Hematopoiesis; HMR: High Molecular Risk; IPSS: International Prognostic Scoring System; DIPSS: dynamic IPSS; PV: Polycythemia Vera; ET: Essential Thrombocythemia; GIPSS: Genetically-inspired Prognostic Scoring System; MIPSS70: Mutation and karyotype-enhanced International Prognostic Scoring System for Transplant-age Patients; MIPSS70+ Version 2.0: The karyotype-Enhanced MPPSS70.
Myelofibrosis may present as a primary disorder (PMF) or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV or post-ET MF . PMF is a hematopoietic stem-cell–derived clonal myeloproliferation that belongs to the category of myeloproliferative neoplasm . It has an incidence of about 0.58 new cases per 100.000 person-years, and a prevalence of 6 per 100.000 person-years. Median age at diagnosis is 67 years, with no significant difference in sex distribution . Aberrant cytokine production by clonal cells and host immune reaction are assumed to contribute to PMF associated bone marrow stromal changes  (including reticulin fibrosis) , ineffective erythropoiesis, EMH, cachexia and constitutional symptoms . Clinical manifestations in PMF include severe anemia, marked hepatosplenomegaly, constitutional symptoms (e.g., fatigue, night sweats, fever), cachexia, bone pain, splenic infarct, pruritus, thrombosis and bleeding. Ineffective erythropoiesis and EMH are the main causes of anemia and organomegaly, respectively .
Diagnosis of MF is currently based on the World Health Organization 2016 criteria, which include bone marrow morphology and presence of the driver mutations JAK2, CALR or MPL in ~ 90% (50% to 60%, 15%-20% and 5%-10% respectively) of the patients. Their presence is supportive but not essential for diagnosis. It is generally believed that driver mutations are essential for the MPN phenotype . About 10% of patients do not develop any known mutation and are considered to have ‘triple-negative’ MF . In addition to driver mutations, 80% of PMF patients harbor other DNA variants in myeloid genes, including ASXL1, TET2, EZH2, SRSF2, DNMT3A, U2AF1, and IDH1/IDH2,
often in multiple combinations . These mutations might contribute to disease progression and leukemic transformation . ASXL1, SRSF2, EZH2, and IDH1/IDH2 mutations are considered high–molecular risk (HMR) mutations; their prognostic relevance is further amplified by their number in an individual patient . Patients with mutations in ≤2 non-canonical genes had 9-fold higher odds of spleen response to ruxolitinib compared to those with ≥3 mutations in such genes .
PMF has a chronic disabling course  and shortened survival . Disease complications include symptomatic portal hypertension that might lead to variceal bleeding or ascites and non-hepatosplenic EMH that might lead to cord compression, ascites, pleural effusion, pulmonary hypertension or diffuse extremity pain. Causes of death include leukemic progression in approximately 20% of patients, consequences of cytopenias including infection or bleeding and comorbid conditions including cardiovascular events .
The prognostic score IPSS, is applicable at diagnosis; DIPSS and DIPSS-plus, can be applied at any time during follow up. These 3 prognostic scoring systems refer to age, constitutional symptoms, anemia, white blood cell counts, and percentage of peripheral blood blasts. DIPSS-plus incorporates 3 additional independent risk factors: red blood cell transfusion requirement, platelet counts <100 × 109/L, and an unfavorable karyotype . The prognostic scores: IPSS, DIPSS, and DIPSS-plus do not perform as well for post-ET or post-PV MF patients . Three new
prognostic systems have been recently introduced: GIPSS which
is based exclusively on mutations and karyotype , MIPSS70
is best utilized in the absence of cytogenetic information but
presence of molecular information  and MIPSS70+ version 2.0
which utilizes both genetic and clinical risk factors . HMR, or
cytogenetic abnormalities, are used to refine prognosis and to aid
decisions regarding eligibility for stem cell transplant . GIPSS
was also shown to predict leukemic transformation .
Observation alone is reasonable for MIPSS70+ version 2.0
“low” and “very low” risk disease (estimated 10-year survival
65%-92%)  and intermediate-risk disease in the absence of
treatment-requiring symptoms .
A preferred treatment option for MIPSS70+ version 2.0
“high” and “very high” risk disease (estimated 10-year survival
0-13%)  since it can induce molecular remission and complete
resolution of bone marrow fibrosis. Failure to achieve molecular
remission on day 180 post allograft is associated with subsequent
clinical relapse. Bone marrow fibrosis regresses rapidly after
allogeneic SCT. About 60% of the patients have a complete or
nearly complete remission of bone marrow fibrosis on day+100
and the percentage of patients increased to 90% at day+180 . A
careful selection of patients according to disease and transplantspecific
risk factors is mandatory .
participation in a clinical trial might be the best approach
in patients with intermediate risk disease (estimated 10-year
survival 30%) requiring treatment . Imetelestat is a telomerase
inhibitor that shows the most intriguing results among the drugs
tested in MF. Response rates were 32% among patients without
an ASXL1 mutation. Complete response was 38% among patients
with a mutation in SF3B1 or U2AF1. Momelotinib (MMB, GS-0387,
CYT387) is a JAK1 and JAK2 inhibitor undergoing phase-3 study.
Anemia and spleen responses were 59% and 48%, respectively.
Most patients experienced constitutional symptoms improvement.
Everolimus is an mTOR inhibitor in a phase 1/2 study. More than
50% reduction in splenomegaly occurred in 20% of the evaluated
patients and the constitutional symptoms response was 69%.
Drug effect on anemia was modest and on JAK2V617F burden was
Symptom-directed conventional drug therapy, radiotherapy,
or splenectomy is advised in MIPSS70 + version 2.0 intermediaterisk
patients  or higher risk patients that are not eligible for
SCT or clinical trial participation . These treatment options
including use of JAK2 inhibitors  are mostly palliative and
unlikely to modify the natural history of the disease or prolong
survival . They should not be used in the absence of clear
treatment indication .
Anemia is best managed by erythropoiesis promoting
drugs such as androgen preparations, danazol, thalidomide,
and prednisone . Pomalidomide (thalidomide analog) might
alleviate anemia in a subset of JAK2-mutated patients without
marked splenomegaly or excess circulating blasts .
i. Localized bone pain and symptomatic non-hepatosplenic
EMH responds to involved-field radiotherapy .
ii. Up to 50% of patients with massive refractory
splenomegaly respond to monthly courses of intravenous
cladribine (2-chlorodeoxyadenosine). Severe reversible
cytopenia being the main toxicity. Interferon-alfa (standard
and pegylated) is not generally recommended since it causes
minimal reduction in splenomegaly .
iii. Splenectomy is indicated in hydroxyurea-refractory
splenomegaly, symptomatic portal hypertension,
thrombocytopenia and frequent red blood cell transfusions
. Older age, leukocytosis, excess circulating blasts, and
transfusion need are risk factors for inferior post-splenectomy
survival . Perioperative complications included infections,
abdominal vein thrombosis and bleeding. Approximately
10% of patients experienced progressive hepatomegaly and
29% experienced thrombocytosis after splenectomy. Overall
perioperative mortality rate was 9%. Median survival after
splenectomy was 19 months .
iv. Ruxolitinib (JAK inhibitor) is effective in alleviating
constitutional symptoms and marked splenomegaly. Sooner
or later, most patients become refractory to both hydroxyurea
and ruxolitinib, and might require splenectomy .
The mechanism of action of ruxolitinib is based on its
nonspecific ability to suppress inflammatory cytokines. Long-term
outcome disclosed a 92% treatment discontinuation rate after
a median time of 9.2 months. Withdrawal symptoms occurring
during ruxolitinib treatment discontinuation are characterized
by acute relapse of disease symptoms, accelerated splenomegaly,
worsening of cytopenias and occasional hemodynamic
decompensation including a septic shock like syndrome .
Absence of consistent molecular and/or pathologic responses
in the tested JAK inhibitors in the clinic is proposed to be due to the
frequency of mutations in non-canonical MPN-relevant genes (e.g.
ASXL1, SRSF2), inadequate drug exposure and the highly variable
JAK2V617F variant allele frequency (1-100%), higher levels being
seen in post-ET/PV MF than in PMF. The proposed heterodimeric
JAK-STAT activation despite sustained JAK2 inhibition may play
a role. JAK inhibitors may be more efficacious if used earlier in
the proliferative/cellular phase, where, there may be favorable
changes in BM architecture .
Allogeneic SCT in PMF is currently associated with at least
50% rate of transplant-related deaths or severe morbidity (e.g.
Graft vs. host disease) regardless of intensity of conditioning
regimens used. There is much interest in evaluating the use of JAK
inhibitors before Allogeneic SCT . Transplanted patients after
clinical response to JAKi showed improvement of their symptom
burden, performance status and reduction of splenomegaly, thus
facilitating more intensive therapeutic approaches, augmented
hematological recovery and improved graft function compared
with those who demonstrated loss of response or progressive
disease . In addition, ruxolitinib is hypothesized to modulate
T-, natural killer, and dendritic cell function and may alter the
incidence and perhaps grade of graft-versus-host disease rates.
Drawbacks of ruxolitinib therapy before SCT include drug-related
cytopenia, rare risk of tumor lysis syndrome or unexpected
toxicity. Longer follow-up is required to determine later outcomes
Clinical (e.g., anemia/thrombocytopenia grade, spleen size),
biological (e.g., poor-risk molecular or cytogenetic abnormalities),
and patient-specific (e.g., age, performance status) factors, and
the reason(s) for JAK inhibitor failure (e.g., inadequate dosing
due to drug-related toxicity) has to be considered in JAK inhibitor
therapy failure. Symptom based approach is frequently necessary
in SCT-ineligible patients and absence of an identifiable treatment
target. An agent with a novel mode of action is preferred If JAK
inhibitor failure relates to dose-limiting toxicity. Addition of
interferon-α or hydroxyurea to the JAK inhibitor may restore
clinical response although safety data for such combinations is
lacking. In other instances, participation in a clinical trial with an
alternative JAK inhibitor may be appropriate .
Although the therapeutic algorithms for MF have recently
altered, still more researches are needed to find a surrogate
marker for disease response and to fill the gap between molecular
profile of the patients and their application in clinical practice.